Crosslinker enhanced repair of connective tissues

ABSTRACT

A protein crosslinker delivery device includes a body and a protein crosslinker held in a synthetic or natural biodegradable polymer. The body, a coating on the body, or an attachment to the body can contain the protein crosslinker holding biodegradable polymer. The release rate of the crosslinker and total amount of crosslinker released can be controlled by varying the concentration of the crosslinker and by varying the composition and structural characteristics of the degradable polymer. Surface eroding, bulk eroding and naturally occurring biodegradable polymers can be used in conjunction with a variety of nontoxic or minimally-toxic protein crosslinking agents. The devices can be used to treat mechanically damaged, deformed, and nutritionally deficient connective or soft tissues such as the knee meniscus, the spinal disc, the cornea, ligaments and tendons, the soft palate, and skin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application Ser. No. 61/771,248 filed on Mar. 1, 2013, and is a continuation-in-part of application Ser. No. 13/700,091, filed on Dec. 13, 2012, which is a continuation-in-part of application Ser. No. 12/715,737, filed on Mar. 2, 2010, which is a divisional of application Ser. No. 11/712,684, filed Feb. 28, 2007. This application is also a continuation-in-part of application Ser. No. 11/975,072, filed Oct. 17, 2007, which is a continuation-in-part of application Ser. No. 11/726,790, filed Mar. 22, 2007. This application also claims the benefit of Provisional Patent Application No. 61/348,977, filed on May 27, 2010. All of the foregoing applications are incorporated by reference herein.

FIELD OF THE INVENTION

This document relates to protein crosslinking reagents for the surgical repair of injuries and diseases of connective tissues in humans or animals.

RELATED ART

This document relates to a novel device and method for repairing injury and disease of the connective tissues or soft tissues such as the knee meniscus. Other connective and soft tissues that can be repaired by this device include, but are not limited to, the shoulder capsule, tendons, ligaments, the intervertebral disc, the soft palate, the cornea and skin.

The menisci of the knee are a pair of crescent-shaped fibrocartilaginous structures attached to the planar apical surface of the tibia. They contact the outer region of the femoral articular cartilage surface and as such play an important role in both load transmission and in maintaining the stability of the joint.

While 65-75% of the mass of the menisci consists of water, the remaining constituents are primarily proteins, with the most common (75%) being type I collagen. Damage to this tissue is one of the most common causes of knee injury and results in surgery to some 850,000 patients per year in the US. Symptoms of meniscal tears are primarily localized pain and swelling, but in cases where fragments of the damaged meniscus lodge between the articulating surfaces of the joint, catching sensations and (in the worst case) locking of the joint can occur.

The first line of treatment for meniscal tears is non-surgical, e.g. rest, icing, physical therapy and/or non-steroidal anti-inflammatory drug (NSAID) treatment. Surgery is indicated for patients who do not respond to physical therapy, who cannot or are unable to sacrifice the time required for potentially unsuccessful therapy and for those with locked joints.

Surgery is most commonly, but not exclusively, conducted arthroscopically to minimize further damage to the joint and to decrease patient recovery times. Damage to the outer periphery of either meniscus heals more readily than that to the inner portions, due to the lack of vasculature in the inner portion of the meniscus. For this reason, tears of the inner meniscus are usually excised in a procedure known as a partial meniscectomy. In the remaining cases, tears are repaired using either suture or a variety of commercially available fixing devices, such as arrows, darts and tacks, in order to facilitate healing of the tear. These devices are generally constructed using biodegradable polymers, such as poly(lactic acid) or poly(glycolic acid), so that no subsequent surgery is required for their removal.

Although arrows, darts and tacks provide temporary support to the tissue as it heals, they are generally not as strong as sutures. However, because their use results in substantially reduced operating times and risk of complications to the patient, they are increasingly gaining favor.

While the above represents the most common approaches to the treatment of meniscal tears, other therapeutic modalities for meniscal repair can be used or are being explored experimentally. These include: stem cell therapy; trephination from the vascular to avascular region to facilitate greater nutrient flow and promote in-growth of vasculature; micro-fracture of the intercondylar notch which may release growth factors or autologous stem cells to aid in the repair process; thermal welding of the tear; enhancement of fibroblast proliferation using radio frequency (RF) radiation; use of fibrin clots to both provide stimuli for both chemotaxis and proliferation of regenerative cells, sometimes in conjunction with laser soldering; meniscal or synovial rasping to promote healing via the release of growth factors from the tissue; and synovial flap grafting at the repair site to provide vasculature.

In addition, meniscal replacement using both artificial implants and allografts is becoming a treatment option in the case of severe tears where meniscectomy is the only other treatment option. In this respect, the possibility of stabilizing allografts and artificial implants against biodegradation using ex vivo protein crosslinking has been explored. The inventors are, however, unaware of any prior art with regard to cros slinking of the native meniscus in situ.

SUMMARY

In accordance with the purposes and benefits described herein, a protein crosslinker delivery device is provided for treating a connective tissue injury. That device is broadly described as comprising a body and a protein crosslinker held in a synthetic or natural biodegradable polymer. For the purposes of this application, a biodegradable polymer is a polymeric material that degrades by any mechanism. Such degradation is generally grouped into polymers that degrade primarily by surface erosion or primarily by bulk erosion. The tendency toward surface or bulk erosion is not exclusive for a material and many polymers undergo a combination of both. For the purposes of this application, a surface erodible polymer refers to a polymer that primarily degrades in vivo from the external surface in a layer by layer manner with minimal water penetration. This degradation occurs within days or hours with the material undergoing chemical hydrolysis or dissolution. For purposes of this application, a bulk erodible polymer refers to a polymer that primarily degrades in vivo throughout the whole volume of the polymer with high water penetration. This degradation occurs within hours to months by the material undergoing chemical hydrolysis. Both surface eroding and bulk eroding polymers have been included under the common terms “biodegradable polymer” or “erodible polymers” in this application. The surface erodible polymer may be selected from a group of polymers consisting of polyanhydrides, poly(ortho esters), association polymers consisting of cellulose acetate phthalate and Pluronic, poly(trimethylene carbonate), polyvinyl alcohol, alginate, maltodextrins, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, and mixtures thereof. The bulk erodible polymer may be selected from a group of polymers comprising poly(lactic acid) (PLA), poly(glycolic acid) (PGA), copolymers of PLA and PGA (PLGA), polydioxanone, poly(propylene fumarate), polycaprolactone , poly(β-amino ester) hydrogels and mixtures thereof. The biodegradable polymers could also be selected from naturally occurring polymers comprising alginate, dextran, chitosan, hyaluronic acid, cyclodextrin, collagen and mixtures thereof. Further, the protein crosslinker is selected from a group of crosslinkers consisting of genipin (GP), methylglyoxal (MG), proanthrocyanidin (PA), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), L- or D-threose, transglutaminase and mixtures thereof.

One useful embodiment the device further includes a basic salt to neutralize acidic byproducts generated during degradation of the polymer. That basic salt may be selected from a group of salts consisting of calcium carbonate, calcium hydroxyapatite, sodium bicarbonate, 2-amino-2-hydroxymethyl-prysane-1,3-diol(tris), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) and mixtures thereof.

In yet another useful embodiment, the body is made of a biodegradable polymer with the crosslinking agent embedded throughout its volume. In still another useful embodiment, the body is made up of a biodegradable polymer with or without a crosslinking agent embedded in it with a coating of the protein crosslinker held in the same or a different biodegradable polymer. In a related embodiment, a nondegradable material without crosslinking agent is coated by a protein crosslinker held in a biodegradable polymer. In a related embodiment, the body is a suture made of collagen (plain or chromic) and is coated by a protein crosslinker held in a biodegradable polymer.

In one possible embodiment, the biodegradable polymer fully degrades within 240 hours. In another possible embodiment, the biodegradable polymer fully degrades within 72 hours. In still another possible embodiment, the biodegradable polymer fully degrades within 48 hours. In yet another possible embodiment the biodegradable polymer fully degrades within 24 hours. In still another possible embodiment the biodegradable polymer fully degrades within 10 hours.

In one possible embodiment, the device is a patch. In another possible embodiment the device is an arrow. In yet another possible embodiment, the device is a dart. In still another possible embodiment, the device is a tack. Still further, in another possible embodiment, the device is a suture. In any of the possible embodiments, the body may include an attachment made from the protein crosslinker held in a biodegradable polymer.

In another embodiment, the device is fabricated from a metal, such as stainless steel or a titanium alloy, in the form of, for example, a staple, pin or wire, and is coated with a biodegradable polymer containing a crosslinking agent.

In another embodiment, the device is an in situ polymerizable injectable formulation containing biodegradable polymer and crosslinking agent in the appropriate solvent. These crosslinker-containing biodegradable polymer solutions would precipitate on injection in vivo and form a temporary layer/filling/scaffold of the biodegradable polymer with crosslinker embedded in it.

In another embodiment, the device is fabricated in the form of biodegradable polymer particles in a suspension with the particles encapsulating a crosslinking agent. These microspheres/microparticles in a suspension can be injected at the appropriate site for release of protein cros slinking agents. The particles can be kept dispersed within the fluid medium by mechanical (fluid movement), electrochemical or chemical factors. In still another useful embodiment, the device is fabricated in the form of nanoscale delivery systems such as liposomes encapsulating a protein crosslinking agent for rapid release. The liposomes can be with or without surface ligands for attaching the liposome to the tissue that is targeted for the cros slinking treatment.

In another embodiment the protein crosslinking agent is embedded in, or coated onto a hard contact lens and used for treatment of the cornea or sclera of the eye. As one example, in the case of astigmatism, the hard contact lens molds or helps in constraining the cornea to an appropriate shape, and the released crosslinking agent fixes the cornea in the constrained shape after removal of the lens.

In accordance with yet another aspect, a method is provided for treating an injury to a connective tissue of a patient. That method comprises contacting the injured connective tissue with a protein crosslinker delivery device as described herein.

These and other embodiments of the device and method will be set forth in the description which follows, and in part will become apparent to those of ordinary skill in the art by reference to the following description and referenced drawing figures.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the present invention, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which:

FIG. 1 is a side elevational view of a protein crosslinker delivery device in the form of a dart connected to a suture.

FIG. 2 is a cross sectional view of a protein crosslinker delivery device in the form of a tack.

FIG. 3 illustrates a patch and the placement of the patch on an injured meniscus.

FIG. 4 illustrates another embodiment of a protein crosslinker delivery device including an attachment made from a protein crosslinker held in a biodegradable polymer.

DETAILED DESCRIPTION

Reference is made to FIG. 1 illustrating a protein crosslinker delivery device 10 in the form of a dart. The device 10 includes a body 12 including a distal end having a pointed tip 14 and a proximal end 16 having a bore or other means for attaching to a suture 18. The body 12 also includes barbs 20 which permit distal movement of the device 10 through body tissue while resisting proximal withdrawal. The body 12 is made from a biodegradable or non-biodegradable polymer with or without embedded crosslinkers coated with a protein crosslinker held in a surface erodible or bulk erodible polymer. In one useful embodiment, the erodible polymer fully erodes within 240 hours. In one useful embodiment, the erodible polymer fully erodes within 72 hours. In another useful embodiment, the erodible polymer fully erodes within 48 hours. In yet another useful embodiment, the erodible polymer fully erodes within 24 hours. In still another useful embodiment, the erodible polymer fully erodes within 10 hours.

Depending on the molecular weight/chain length of the polymer, the surrounding environment (acidic or alkaline) and the geometric dimensions, the surface eroding or bulk eroding polymers might undergo degradation over a time period ranging from days to months. As the polymer degrades, it releases crosslinkers that were held therein. Those therapeutic crosslinkers provide mechanical stabilization for, and increased nutrient flow to, the damaged or torn meniscus tissue.

The surface erodible polymers used in the device 10 include but are not limited to polyanhydrides, poly(ortho esters), association polymers consisting of cellulose acetate phthalate and Pluronic (, poly(trimethylene carbonate), polyvinyl alcohol (PVA), alginate, maltodextrins, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrolidone, and mixtures thereof. The bulk erosion polymers used in the device 10 include but are not limited to poly(lactic acid) (PLA), poly(glycolic acid) (PGA), copolymers of PLA and PGA (PLGA), polydioxanone, poly(propylene fumarate), polycaprolactone, poly(β-amino ester) hydrogels and mixtures thereof. The naturally occurring polymers used in the device 10 include but are not limited to alginate, dextran, chitosan, hyaluronic acid, cyclodextrin, collagen and mixtures thereof. Therapeutic protein crosslinkers used in the device 10 include but are not limited to genipin (GP), methylglyoxal (MG), proanthrocyanidin (PA), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), L- or D-threose, transglutaminase and mixtures thereof.

Reference is now made to FIG. 2, which illustrates a protein crosslinker delivery device 50 in the form of a tack. The device 50 includes a body 52 having a pointed end 54 and a head 56. As illustrated, the body 52 includes a coating 58. The body 52 may be made from a biocompatible material with or without crosslinkers while the coating may be made from a biodegradable polymer containing crosslinkers.

In one possible FIG. 2 embodiment, the body 52 is made from a biocompatible material that is nonabsorbable and thus forms a permanent implant. Such a polymer material may include but is not limited to polyvinylacetate, polyvinylchloride, polypropylene, polyetheretherketone (PEEK), polysulfone, polyethersulfone, polytetrafluoroethylene, polyethylene, polyurethane, polyetherimide and polycarbonate. Such a body 52 may or may not include pores or other surfaces or porous coatings or attached filaments or other attachments for receiving and holding the coating 58 including the biodegradable polymer and crosslinkers. In another embodiment, the device is made from a biocompatible metal, such as (but not limited to) stainless steel, titanium, tantalum, titanium alloys and cobalt alloys. Metal devices may also include pores or additional porous coatings or other surfaces or attachments for receiving and holding the coating containing the biodegradable polymer and crosslinkers.

In an alternative FIG. 2 embodiment, the body 52 is made from a biodegradable polymer, such as poly(lactic acid) or poly(glycolic acid). As noted above, such polymers degrade over the course of weeks or months. Thus, they can remain in place in the body 52 for an extended period of time to provide added support for the injured knee meniscus. Where the biodegradable polymer includes or incorporates therapeutic crosslinkers, the body provides further release of those therapeutic crosslinkers over an extended period of time compared to the crosslinkers that are rapidly released from the erodible coating 58 on the body.

In any of the embodiments, the therapeutic crosslinkers released from the device 10, 50 enter into, and react with, the tissue to form crosslink bonds including covalent bonds. These bonds serve to both strengthen the tissue against further and/or future tearing and also increase the permeability of the tissue to nutrients from the blood supply, thereby enhancing the natural healing process. In addition, and in the case of the knee meniscus, the increase in tissue permeability conferred by the crosslinking will increase the proportion of meniscal tear patients who can be treated surgically since healing using current methods can only occur in regions with sufficient vascular nutrient supply.

While a dart and a tack are illustrated in FIGS. 1 and 2, it should be appreciated that the device can take a number of other forms including, for example, a patch, an arrow or even a suture as illustrated at 18 in FIG. 1.

A method of treating an injury to a knee meniscus of a patient involves contacting the injured area of the meniscus with the device 10, 50. For example, if the device is in the form of a patch 100 (see FIG. 3), it may be attached to the meniscus tissue M using fixation devices, such as arrows, darts, tacks or sutures. Alternatively, the patch 100 may be attached using a suitable biocompatible adhesive. Non-limiting examples of suitable adhesives include poly(glycerol-co-sebacate acrylate), oleic methyl esters or alkyl ester cyanoacrylates.

Solid or liquid crosslinker may be incorporated into the device 10, 50, 100 by addition to the molten polymer prior to casting, molding or spinning. Alternatively the crosslinker may be co-solubilized with the polymer in a suitable solvent (for example, acetone, N-methylpyrrolidone, dimethyl sulfoxide or solvent mixture and then incorporated into the device 10, 50, 100 by removal of the solvent by evaporation or by precipitation (for example, by the addition of ethanol) of the polymer as described previously. The crosslinker and polymer may also be solubilized separately and mixed prior to precipitation in either the same solvent or different (miscible) solvents. Also, the solid crosslinker may also be mixed into the polymer gum formed by precipitation of solubilised polymer prior to molding. The rate of crosslinker release can be controlled by varying the amount or concentration of the crosslinker incorporated into the device as well as by selecting polymers or other materials with differing in vivo degradation rates, and by varying the concentrations or molecular weight/chain length of the polymers.

Alternatively, the crosslinker may be co-solubilized with the polymer in a suitable solvent, solubilized separately in the same solvent and then mixed, or solubilized separately in different miscible solvents and then mixed, and a pre-formed fixation device immersed in this solution. Following removal of the fixation device and evaporation of the solvent, a fixation device containing an outer layer of erodible and/or biodegradable polymer-embedded crosslinker will be produced. The polymer in the outer layer may be different from that of the underlying device both in chain length and/or composition and may be varied, for example, in order to provide different release rates of crosslinker as needed. Additionally, the rate, duration and extent of crosslinker release can be controlled by varying the amount or concentration of the crosslinker incorporated into solvent solution (and therefore the outer layer of the device), by sequential dipping/drying of the fixation device into the crosslinker/polymer/solvent mixture to produce different thicknesses of crosslinker containing polymer at the surface of the device, or by changing the type of polymer or the molecular weight of the polymer used in the coating. Additionally, several crosslinker impregnated outer layers may be used with varying crosslinker amount or concentration and polymer compositions such that the rate of release of crosslinker can be varied as desired. For instance, an initial high rate of crosslinker release can be followed by a low rate of crosslinker release for an extended length of time.

Additionally, in cases where the crosslinker is insufficiently soluble in the solvent used to solubilize the polymer to attain the desired concentration in the final device, additional cosolvents may be added to increase the concentration of the crosslinker. This cosolvent can be less volatile than the solvent used to solubilize the polymer. For example, possible cosolvents used to solubilize the crosslinker genipin in acetone for incorporation into a PLGA coating include, but are not limited to, dimethyl sulfoxide, dimethyl formamide and N-methylpyrrolidone.

Furthermore, in the case of sutures, one or more plasticizers may be added to the coating solution in order to maintain the flexibility of the coating layer and so prevent its cracking and flaking during use. Non-limiting examples of suitable plasticizers are polyethylene glycol (PEG), tributyl citrate, triethyl citrate, glycerine, diethyl phthalate, dibutyl sebacate, triacetin, acetyl tributyl citrate.

It has been previously shown that many crosslinking reagents act less efficiently at low pH. In addition, some biodegradable polymers, including poly(lactic acid) and poly(glycolic acid), degrade to form acidic compounds. In fact, tissue acidification during polymer breakdown has been a concern previously, and incorporation of basic inorganic salts into the polymer matrix has been shown to be effective in maintaining an elevated pH.

In some embodiments, in cases where low-pH sensitive crosslinkers (for example, genipin, methylglyoxal) are used in conjunction with polymers that degrade to form acidic compounds, for example poly(lactic acid) and/or poly(glycolic acid), basic salts are also incorporated as solid suspensions into the erodible polymer matrix. Such salts could be inorganic (for example, but not limited to, calcium carbonate, calcium hydroxyapatite or sodium bicarbonate) or organic (for example, but not limited to, 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris) or 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES).

In some embodiments, the crosslinker is impregnated by one of the methods described above into a flat, biodegradable polymer patch 100. The patch 100 could contain pH conditioning agents and multiple layers of crosslinking agents as described above. The patch 100 (which could be rolled up and inserted via a catheter) is laid over the repaired tissue such that crosslinker is delivered to the meniscus as the patch dissolves and while the patch offers some physical protection to the damaged meniscal tissue as it heals. The surface of the patch opposite to the meniscus additionally provides a smooth bearing surface to the articular cartilage of the femur. Such crosslinker eluting patches can also be applied to other connective tissues of the body, such as the shoulder capsule or the plantar fascia of the foot.

A large number of protein crosslinkers could be used in conjunction with the present invention. In particular embodiments, the crosslinker may be a single crosslinker or a combination of two or more crosslinkers. It has been shown that the conditions that confer optimal reactivity of such crosslinkers differ between reagents and that in some cases other chemicals can enhance their reactivity. In addition, some detergents can also enhance the penetration of crosslinkers through collagenous tissues and therefore help to enhance their ability to crosslink the tissue. Thus, some embodiments may include a chemical or detergent, or any combination thereof that enhances the crosslinking ability of the crosslinker.

Referring to FIG. 3, a stylized human knee meniscus M with a “parrot beak” type tear T is depicted. Following surgical repair, a patch 100 of crosslinker-impregnated material is placed over the damaged tissue. The shaded area 5 depicts the position of the patch 100 following attachment. The patch 100 may be coated with an erodible polymer containing crosslinker. The patch 100 may additionally be attached using typical surgical fixation devices or by addition of a suitable biocompatible solvent or adhesive to the side of the patch 100 in contact with the meniscus. Over time crosslinker will diffuse out of the patch 100 and/or the erodible polymer coating on the patch 100 and into the tissue, both strengthening it and facilitating the diffusion of nutrients into the damaged area by increasing the tissue permeability.

While application of the device 10, 50, 100 to the repair of a diseased or damaged meniscus is described and illustrated in detail above, it should be appreciated that the device 10, 50, 100 and method are generally applicable to the repair of diseased or injured connective tissue in both man and animal. For example, an annulus fibrosis fixation device (suture, tack, etc.) with a crosslinker-releasing coating may be used subsequent to discectomy, nucleus implant surgery, or disc herniation to repair the annulus. Also, these same types of devices may have utility in repair of the shoulder capsular tissues, ankle syndesmosis, Achilles tendon, plantar fascia, carpal tunnel sheath (flexor retinaculum), etc. In another possible example, a coating of erodible polymer and crosslinker could be provided on a device for the soft palate such as a Pillar implant or a synthetic or naturally occurring biodegradable or nondegradable suture.

The present invention may be better understood by referring to the accompanying examples, which are intended for illustration purposes only and should not in any sense be construed as limiting the scope of the invention.

EXAMPLE 1

A patch constructed of a biodegradable polymer, such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA) or poly(lactic-co-glycolic acid) (PLGA) is dip-coated with an aqueous solution containing 10% polyvinyl alcohol (PVA) and 100 mM of the crosslinker methylglyoxal (MG) and then allowed to dry at room temperature. The thickness of the MG-impregnated coating can be varied utilizing multiple applications of solution, by varying the concentration (and thus viscosity) of the PVA polymer, or adjusting the rate at which the patch is withdrawn from the PVA-MG solution. The release rate of the MG can be varied by changing the concentration of the PVA polymer and/or that of the MG.

EXAMPLE 2

A patch constructed of a biodegradable polymer, such as PLA, PGA or PLGA, is sprayed with a solution of partially hydrolyzed PVA in ethanol containing 200 mM of the crosslinker genipin (GP) and allowed to dry. The thickness of the GP-impregnated coating can be varied utilizing multiple applications of solution. The release rate or loading of the GP can be varied by varying the concentration PVA and/or GP in the coating solution. These patches can be used for treatment of meniscal repair as shown in FIG. 3.

EXAMPLE 3

A biodegradable meniscal fixation device, such as a tack or dart, is dip-coated with a solution of 15% association polymer composed of cellulose acetate phthalate (CAP) and Pluronic (P)(CAPP) in acetone containing 400 mM GP and allowed to dry. The total crosslinker loading can be controlled by either varying the concentration of the crosslinker in the coating solution or by the application of numerous sequential coatings. The release rate of the crosslinker can also be changed by varying the ratio of CAP:Pluronic or by varying the concentration of CAPP, plasticizer, and/or GP in the coating solution.

EXAMPLE 4

A PGA suture is dip-coated with a solution of 15% association polymer system (CAPP) in acetone containing 400 mM GP and a plasticizer (such as 3% diethyl phthalate or 5% triethyl citrate or tributyl citrate) and allowed to dry. The total crosslinker loading can be controlled by either varying the concentration of the crosslinker in the coating solution or by the application of multiple coatings. The release rate of the crosslinker can also be changed by varying the ratio of CAP:Pluronic or by varying the concentration of CAPP, plasticizer, and/or GP in the coating solution. The PGA sutures coated with a CAPP layer capable of releasing cross linking agent at appropriate dose and desired rate can be used for meniscal repair.

EXAMPLE 5

A PGA suture is dip coated in a polymer solution consisting of 10% PLGA in cosolvent of DMSO/NMP/acetone with 400-3000 mM GP with 1% to 3% plasticizer, such as PEG. The total crosslinker loading can be controlled by either varying the concentration of the crosslinker in the coating solution or by the application of multiple coatings. The release rate of the crosslinker can also be changed by varying the molecular weight of PLGA or the ratio of lactic to glycolic acid in the PLGA copolymer. The PGA sutures coated with a polymer layer capable of releasing crosslinking agent at appropriate dose and desired rate can be used to increase tear resistance of the tissue and thereby avoid wound dehiscence due to suture pull out.

EXAMPLE 6

A polydioxone suture is dip-coated in a polymer solution consisting of 10% PLGA in cosolvent of DMSO/NMP/acetone with 400-3000 mM GP with 1% to 3% plasticizer, such as PEG. The total crosslinker loading can be controlled by either varying the concentration of the crosslinker in the coating solution or by the application of multiple coatings. The release rate of the crosslinker can also be changed by varying the molecular weight of PLGA or the ratio of lactic to glycolic acid in the PLGA copolymer. These polydioxone sutures coated with a polymer layer capable of releasing crosslinking agent at appropriate dose and desired rate can be used to avoid suture pull out from fibrous tissues such as tendons and ligaments.

EXAMPLE 7

Metal wires and staples dip-coated in a polymer solution consisting of 10% PLGA in cosolvent of DMSO/NMP/acetone with 400-3000 mM GP with 1% to 3% plasticizer, such as PEG. The total crosslinker loading can be controlled by either varying the concentration of the crosslinker in the coating solution or by the application of multiple coatings. The release rate of the crosslinker can also be changed by varying the molecular weight of PLGA or the ratio of lactic to glycolic acid in the PLGA copolymer.

EXAMPLE 8

Non-absorbable sutures, such as polypropylene and nylon, are dip-coated in a polymer solution consisting of 10% PLGA in cosolvent of DMSO/NMP/acetone with 400-3000 mM GP with 1% to 3% plasticizer, such as PEG. The total crosslinker loading can be controlled by either varying the concentration of the crosslinker in the coating solution or by the application of multiple coatings. The release rate of the crosslinker can also be varied by varying the molecular weight of PLGA or the ratio of lactic to glycolic acidin the PLGA copolymer.

The foregoing examples have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the embodiments to the precise forms disclosed. Obvious modifications and variations are possible in light of the above teachings. For example, FIG. 4 illustrates a device 200 in the form of a tack including an attachment 202 made from a protein crosslinker held in an erodible polymer. Here, the term attachment should be broadly interpreted to read upon substantially any form of attachment or cover connected to the body 204 of the device 200. Further, it should be appreciated that the device itself or any coating or attachment to the device may be made from a protein crosslinker and a mixture of erodible and biodegradable polymers in a ratio to achieve a desired crosslinker release rate. All such modifications and variations are within the scope of the appended claims when interpreted in accordance with the breadth to which they are fairly, legally and equitably entitled. 

What is claimed:
 1. A protein crosslinker delivery device for treating a connective tissue or soft tissue injury, comprising: a body; and a protein crosslinker held in a synthetic or natural biodegradable polymer.
 2. The device of claim 1 wherein said synthetic biodegradable polymer is selected from a group of surface eroding polymers consisting of polyanhydrides, poly(ortho esters), association polymer systems consisting of cellulose acetate phthalate and Pluronic, poly(trimethylene carbonate), polyvinyl alcohol, maltodextrins, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrolidone, and mixtures thereof.
 3. The device of claim 1 wherein said synthetic biodegradable polymer is selected from a group of bulk erodible polymers consisting of poly(lactic acid) (PLA), poly(glycolic acid) (PGA), copolymers of PLA and PGA (PLGA), polydioxanone, poly (propylene fumarate), cellulose acetate phthalate (CAP), polycaprolactone, poly(β-amino ester) hydrogels and mixtures thereof.
 4. The device of claim 1 wherein said natural biodegradable polymer is selected from a group of naturally occurring polymers consisting of alginate, dextran, chitosan, hyaluronic acid, cyclodextrin, collagen and mixtures thereof.
 5. The device of claim 1 wherein said protein crosslinker is selected from a group of crosslinkers consisting of genipin (GP), methylglyoxal (MG), proanthrocyanidin (PA), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), L-threose, D-threose, transglutaminase and mixtures thereof.
 6. The device of claim 5 further including a basic salt.
 7. The device of claim 6, wherein said basic salt is selected from a group of salts consisting of calcium carbonate, calcium hydroxyapatite, sodium bicarbonate, 2-amino-2-hydroxymethyl-prysane-1,3-diol(tris), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) and mixtures thereof.
 8. The device of claim 5, wherein said body is porous.
 9. The device of claim 5, wherein said body is made of metal and includes a coating consisting of a protein crosslinker held in a biodegradable polymer.
 10. The device of claim 5, wherein said body includes a coating of said protein crosslinker held in a biodegradable polymer.
 11. The device of claim 5, wherein said erodible polymer fully erodes within 240 hours.
 12. The device of claim 5, wherein said erodible polymer fully erodes within 72 hours.
 13. The device of claim 5, wherein said erodible polymer fully erodes within 48 hours.
 14. The device of claim 5, wherein said erodible polymer fully erodes within 24 hours.
 15. The device of claim 5, wherein said erodible polymer fully erodes within 10 hours.
 16. The device of claim 1, wherein said device is selected from a group of structures consisting of a patch, arrow, dart, tack, suture, wire or staple.
 17. The device of claim 1 wherein said body has a coating made from said protein crosslinker held in a biodegradable polymer.
 18. The device of claim 1 wherein said body includes an attachment made in part or in whole from said protein crosslinker held in a biodegradable polymer.
 19. A solution of biodegradable polymer and crosslinker in a non-aqueous solvent, such that when the solvent is diluted by injection into the body the polymer precipitates, solidifies and traps the crosslinker within it.
 20. A method of treating an injury to a connective tissue or soft tissue of a patient, comprising: contacting said injured connective tissue or soft tissue with a protein crosslinker delivery device as set forth in claim
 1. 